Novel small molecule HSP90 inhibitor for the management of atopic dermatitis

用于治疗特应性皮炎的新型小分子 HSP90 抑制剂

• 批准号: 10016726
• 负责人: Gautam Sudhir Ghatnekar
• 金额: $ 25.21万
• 依托单位: REGRANION, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016726
• 关键词: Adaptive Immune System; Address; Adrenal Cortex Hormones; Affect; American; Animal Model; Animals; Anti-Inflammatory Agents; Antihistamines; Atopic Dermatitis; Bioavailable; Biological Availability; Biological Response Modifier Therapy; Biotechnology; Body Surface Area; Cardiovascular system; Chronic; Clinical; Clinical Research; Complex; Disease; Disease Management; Dose; Drug Kinetics; Drug Targeting; Drug Tolerance; Eczema; Emollients; Etiology; Exhibits; Expression Profiling; Foundations; Gene Expression; Heat-Shock Proteins 90; Heterogeneity; Histology; Human; Human Resources; IL17C gene; IgE; Immune; Immunohistochemistry; Immunomodulators; Infectious Skin Diseases; Inflammation; Inflammatory; Injections; Interleukin-13; Interleukin-17; Interleukin-4; Investigation; Investigational Therapies; Lesion; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Oncology; Oral; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Personal Satisfaction; Pharmacology; Phase; Phenotype; Play; Pre-Clinical Model; Property; Proteomics; Pruritus; Psoriasis; Public Health; Quality of life; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Safety; Sampling; Self Administration; Serum; Signal Pathway; Signal Transduction; Skin; Skin Care; Societies; Symptoms; TNF gene; Technology; Therapeutic; Therapeutic immunosuppression; Thick; Time; Topical application; Toxicology; Up-Regulation; Visual; base; chemokine; chronic inflammatory skin; clinical development; clinical investigation; clinically relevant; clinically significant; commercialization; comparative efficacy; compliance behavior; cytokine; design; effective therapy; efficacy evaluation; efficacy study; improved; individualized medicine; inhibitor/antagonist; insight; interleukin-17C; keratinocyte; macrophage-derived chemokine; novel; profiles in patients; protein expression; psychosocial; research and development; research clinical testing; side effect; skin barrier; skin disorder; skin irritation; small molecule; standard of care; therapeutic target; transcriptome sequencing

PROJECT SUMMARY Atopic dermatitis/AD (or ‘atopic eczema’) is a complex, chronic, inflammatory skin disease that affects upwards of 35 million Americans. AD is characterized by a disruption of epidermal-barrier function, inflamed dry and thick skin, severe pruritus and significant impact on patients’ quality of life. Current standard of care involves topical emollients, avoidance of trigger factors and anti-inflammatory strategies including the use of corticosteroids, antihistamines, or broad and recently also specific immunommodulators, such as dupilumab. While broad immunosuppressive therapies can help partly manage the disease, chronic usage results in undesirable side- effects and drug tolerance, resulting in lowered patient compliance and inefficacy. Furthermore, dupilumab is ineffective in a significant portion of patients, suggesting the heterogeneity of AD and need for individualized treatment based on patient profiling. There is a pressing need for the clinical development of targeted immunomodulatory therapeutics, without immunosuppressive side effects, designed to take into account patient profiling and to safely and selectively target pathogenic mediators of AD. HSP90 has been recently classified as an ‘alarmin’ and has key roles in mediating the interplay between the innate and the adaptive immune system as well as known roles in the JAK/STAT and MAP kinase pathway and IL-4, IL-13, and IL-17 signaling. These pathways have key roles in AD-related immune dysregulation. Regranion has recently acquired a potent novel small molecule HSP90 inhibitor (RGRN-305, previously Debio0932) with a good safety profile and attractive pharmacological properties that shows alleviation of psoriatic symptoms, reduced epidermal thickness, and dramatic reduction in levels of TNFα and IL-17, pro-inflammatory cytokines in clinically relevant animal models of psoriasis. These studies laid the foundation for ongoing clinical evaluation in the treatment of moderate-to- severe psoriasis (ClinicalTrials.gov Identifier: NCT03675542) and set a precedence for investigation of HSP90 as a therapeutic target in AD. The focus of this proposal is to accomplish key milestones that will transition this technology for commercialization as a safe and efficacious oral AD therapeutic that targets the upstream proteomic mediators of the disease. The study aims involve i.) rigorous evaluation of the efficacy and mechanism of action of oral RGRN-305 in multiple clinically relevant AD models that incorporate a comparative efficacy study versus corticosteroid treatment, and ii.) characterization of the gene and protein expressions of HSP90 pathway- related markers in normal, nonlesional and AD lesional human skin samples from moderate-to-severe AD patients. A role for HSP90 in the pathogenesis and persistence of AD has not been elucidated. Given that the etiology of AD is multifaceted, characterizing the expression profile of epidermal HSP90 pathway and related cytokines and chemokines will permit insight into the therapeutic potential and opportunity for individualized therapy with RGRN-305.

项目总结 特应性皮炎/AD(或“特应性湿疹”)是一种复杂、慢性、炎症性皮肤病，其影响范围可达以上。 三千五百万美国人。AD的特征是表皮屏障功能紊乱，发炎、干燥和增厚。 皮肤瘙痒严重，严重影响患者的生活质量。目前的护理标准包括局部治疗 润肤剂，避免触发因素和抗炎策略，包括使用皮质类固醇， 抗组胺药，或广泛的，最近也有特异性的免疫调节剂，如杜匹单抗。 虽然很宽泛 免疫抑制疗法可以帮助部分控制疾病，长期使用会导致不良副作用- 影响和药物耐受性，导致患者依从性降低和无效。此外，dupiumab是 在相当一部分患者中无效，表明AD的异质性和个性化的需求 基于患者概况的治疗。靶向药物的临床开发迫在眉睫 免疫调节疗法，无免疫抑制副作用，设计用于考虑患者 并安全和选择性地针对阿尔茨海默病的致病介质。HSP90最近被归类为 在调节先天免疫系统和获得性免疫系统之间的相互作用方面起着关键作用 以及在JAK/STAT和MAP激酶通路以及IL-4、IL-13和IL-17信号转导中的已知作用。这些 信号转导通路在AD相关免疫失调中起关键作用。Regranion最近获得了一部强有力的小说 小分子HSP90抑制剂(RGRN-305，以前的DeBio0932)，具有良好的安全性和吸引力 具有缓解牛皮癣症状、减少表皮厚度的药理作用，以及 临床相关动物模型中促炎细胞因子肿瘤坏死因子α和白介素17水平的显著降低 牛皮癣的症状。这些研究为正在进行的中-中等偏瘫治疗的临床评估奠定了基础 严重银屑病(ClinicalTrials.gov标识符：NCT03675542)，开创了HSP90研究的先河 作为治疗阿尔茨海默病的靶点。这项提议的重点是完成将过渡到这一点的关键里程碑 作为一种针对上游人群的安全有效的口服AD治疗药物的商业化技术 疾病的蛋白质组学介体。这项研究的目的涉及i.)严格评估疗效和作用机制 口服RGRN-305在多种临床相关AD模型中的作用 与皮质类固醇治疗相比，以及ii。)热休克蛋白90途径基因和蛋白表达的研究 中重度AD患者正常皮肤、非皮损和AD皮损中相关标志物的检测 病人。热休克蛋白90在阿尔茨海默病的发病机制和持续性中的作用尚未阐明。考虑到 阿尔茨海默病的病因是多方面的，表征了表皮HSP90途径和相关基因的表达谱 细胞因子和趋化因子将使我们能够洞察个体化的治疗潜力和机会 使用RGRN-305进行治疗。